Huprine–Tacrine Heterodimers as Anti-Amyloidogenic Compounds of Potential Interest against Alzheimer’s and Prion Diseases
| Autor: | Axel Bidon-Chanal, Elisabet Viayna, Miriam Ratia, Carles Galdeano, M. Victòria Clos, Vincenza Andrisano, Cristina Minguillón, Gema C. González-Muñoz, Júlia Relat, Pelayo Camps, Albert Badia, F. Javier Luque, Diego Muñoz-Torrero, Irene Sola, Manuela Bartolini, Francesca Mancini, Xavier Formosa, Mario Salmona, M. Isabel Rodríguez-Franco |
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| Přispěvatelé: | Galdeano C., Viayna E., Sola I., Formosa X., Camps P. Badia A., Clos M.V., Relat J., Ratia M., Bartolini M., Mancini F., Andrisano V., Salmona M., Minguillon C., Gonzalez-Munoz G. C., Rodriguez-Franco M. I., Bidon-Chanal A., Luque F. J., Munoz-Torrero D. |
| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Molecular model Prions Peptide Heterocyclic Compounds 4 or More Rings AMYLOID BETA-PEPTIDES Permeability Prion Diseases ALZHEIMER DISEASE/DRUG THERAPY CHOLINESTERASE INHIBITORS Mice chemistry.chemical_compound Alzheimer Disease Drug Discovery medicine Animals Humans Structure–activity relationship STRUCTURE-ACTIVITY RELATIONSHIP Butyrylcholinesterase chemistry.chemical_classification Brain Membranes Artificial Stereoisomerism Acetylcholinesterase Peptide Fragments Recombinant Proteins In vitro chemistry Biochemistry Tacrine Aminoquinolines Molecular Medicine PRION DISEASES/*DRUG THERAPY Ex vivo medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 55:661-669 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm200840c |
| Popis: | A family of huprine-tacrine heterodimers has been developed to simultaneously block the active and peripheral sites of acetylcholinesterase (AChE). Their dual site binding for AChE, supported by kinetic and molecular modeling studies, results in a highly potent inhibition of the catalytic activity of human AChE and, more importantly, in the in vitro neutralization of the pathological chaperoning effect of AChE toward the aggregation of both the beta-amyloid peptide (Abeta) and a prion peptide with a key role in the aggregation of the prion protein. Huprine-tacrine heterodimers take on added value in that they display a potent in vitro inhibitory activity toward human butyrylcholinesterase, self-induced Abeta aggregation, and beta-secretase. Finally, they are able to cross the blood-brain barrier, as predicted in an artificial membrane model assay and demonstrated in ex vivo experiments with OF1 mice, reaching their multiple biological targets in the central nervous system. Overall, these compounds are promising lead compounds for the treatment of Alzheimer's and prion diseases. |
| Databáze: | OpenAIRE |
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